The endoplasmic reticulum (ER) is the site of folding and maturation for virtually all secreted and membrane proteins of the cell. The demand for secreted protein production fluctuates dramatically in cells in response to developmental or environmental cues. Demand for increased ER protein folding capacity is sensed by the Unfolded Protein Response signaling pathway (UPR), conserved in all eukaryotes. Activation of the UPR pathway results in increased expression of ER chaperones and other protein folding components in order to increase ER protein folding capacity. As ER cannot be generated de novo but must be inherited by daughter cells, we became interested in mechanisms that assure the functional quality of inherited ER. Recently, we have found that: (1) functionally stressed ER is not transmitted to daughter cells, and (2) results in block in cytokinesis in S. cerevisiae. We confirmed that blocked cytokinesis is not due to ER-stress induced global defects in the localization of secretory pathway components critical for cell division. Moreover, the cytokinesis block is not dependent on the canonical UPR pathway, occurring even in IRE1-defective cells. (3) We also find a provocative phenotype: ER stress disrupts the dynamics of the septin complex, which normally assembles at the mother/daughter cell bud neck and mediates cell separation during cytokinesis. Most recently, we have identified the SLT2 MAP kinase as playing an important role in coordinating ER function with ER inheritance. Cells lacking SLT2, when subjected to ER stress, are no longer blocked for cytokinesis, have normal septin ring dynamics, and transmit stressed ER to their daughter cells. However, such cells are unable to sustain more than a subsequent rounds of cell division, indicating a critical need for functional ER. Taking these results together, we hypothesize the existence of an ER- stress surveillance mechanism that ensures the fidelity of ER transmitted to daughter cells, such that information on ER functional capacity is communicated, either directly or indirectly, to the septin complex and to components that affect ER movement during inheritance. In this proposal we propose to: (1) determine which stage of the ER inheritance process is effected by ER stress, (2) investigate the molecular nature of the aberrant septin complex behavior caused by ER stress, (3) analyze the molecular role of SLT2 in cytokinesis and cER inheritance, and (4) map our existing as well as new components into the pathway that comprises the ER stress surveillance mechanism. The failure to regulate ER functional capacity is increasingly recognized as contributing to the pathophysiology of a number of human diseases, including certain cancers. Thus, knowledge of the cellular mechanisms assuring the maintenance and transmission of a functionally competent ER will be invaluable towards the development of previously unrecognized strategies for therapeutic intervention.